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Abstract:

The present invention describes the methods of using incretin mimetics
such as GLP-1 receptor agonists, particularly exenatide, to treat short
bowel syndrome and spastic or hyperactive esophageal motor disorders.

Claims:

1. A method for treating spastic or hyperactive esophageal motor disorder
in a subject in need thereof, comprising: providing an incretin mimetic;
and administering a therapeutically effective amount of the incretin
mimetic to the subject to treat the spastic or hyperactive esophageal
motor disorder.

2. (canceled)

3. The method of claim 1, wherein the spastic or hyperactive esophageal
motor disorder is selected from the group consisting of esophageal spasm,
nutcracker esophagus, achalasia and combinations thereof.

14. A method of normalizing bowel function in a subject in need thereof,
comprising: providing an incretin mimetic; and administering a
therapeutically effective amount of the incretin mimetic to the subject.

15. The method of claim 14, wherein normalizing bowel function comprises
reducing the number of bowel movements in the subject.

25. A kit for treating a gastrointestinal disorder in a subject in need
thereof, comprising: an incretin mimetic; and instructions to administer
a therapeutically effective amount of the incretin mimetic to the
subject.

27. The kit of claim 25, wherein the gastrointestinal disorder is
selected from the group consisting of short bowel syndrome, spastic or
hyperactive esophageal motor disorder and combinations thereof.

28. The kit of claim 26, wherein the GLP-1 receptor agonist is exenatide.

Description:

FIELD OF INVENTION

[0001] This invention relates to the use of GLP-1 receptor agonists to
treat short bowel syndrome and spastic or hyperactive esophageal motor
disorders.

BACKGROUND

[0002] All publications herein are incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by reference.
The following description includes information that may be useful in
understanding the present invention. It is not an admission that any of
the information provided herein is prior art or relevant to the presently
claimed invention, or that any publication specifically or implicitly
referenced is prior art.

[0003] One gastrointestinal disorder is short bowel syndrome (SBS), also
referred to as small intestine insufficiency. SBS is a serious, often
life-threatening, medical problem resulting in severe diarrhea and
nutritional deprivation. Injury or trauma may cause short bowel syndrome;
for example, surgical removal of a large portion of the small intestine.
The removal may result in the lack of surface area in the remaining bowel
to absorb enough nutrients from food. Short bowel syndrome may also be
caused by the small intestine's loss of absorptive function due to
diseases; for example, Crohn's disease and cancer. Though rare, short
bowel syndrome may be congenital and is often referred to as Congenital
Short Bowel Syndrome.

[0004] Other symptoms of short bowel syndrome include, but are not limited
to abdominal pain, steatorrhoea, greasy stools, edema, weight loss, and
fatigue. The symptoms result from a lack of absorptive surface and loss
of the braking mechanisms controlling the proximal gut. One of the
missing, distally produced, peptides that control the proximal gut is
glucagon-like peptide-1 (GLP-1). Complications due to short bowel
syndrome include weight loss, malnutrition, weakened bones, gallstones,
bacterial overgrowth, metabolic acidosis and kidney stones.

[0005] Currently available treatments for short bowel syndrome aim to
relieve its symptoms. A high-calorie and low-residue diet may be
prescribed. Medications attempt to lengthen the time the nutrients are
available in the intestine for absorption. In instances wherein normal
feeding is not delivering enough nutrients, parenteral nutrition may be
necessary. Surgery, such as intestinal lengthening or tapering, may be
performed.

[0006] Currently, there is no cure for short bowel syndrome and treatment
options are not completely effective for all patients. Thus, there is a
need in the art for alternative or improved methods and compositions to
treat short bowel syndrome.

[0007] Other gastrointestinal disorders include spastic or hyperactive
esophageal motor disorders which may limit the delivery of food and
liquid, as well as cause painful symptoms. Examples of spastic or
hyperactive esophageal motor disorders include, but are not limited to,
esophageal spasms, nutcracker esophagus and achalasia.

[0008] Esophageal spasms are uncoordinated series of muscle contractions
that prevent the proper traveling of food into the stomach. Some signs
and symptoms of esophageal spasms include chest pain, difficulty
swallowing, painful swallowing, a sensation that an object is stuck in
the throat, regurgitation, and heartburn. Short term treatment of
esophageal spasms may involve the use of medications to relax the
esophageal muscles. Long term treatment of esophageal spasms may include
management of any contributing health condition (e.g., gastroesophageal
reflux disease ("GERD")), medications, and alteration of eating habits.

[0009] Nutcracker esophagus is an abnormality wherein swallowing
contractions are too powerful. Symptoms of nutcracker esophagus include
chest pain, dsyphagia, and heartburn. Treatment options for nutcracker
esophagus include anti-reflux therapy to treat an underlying cause (e.g.,
GERD), use of medications such as nitrates or calcium channel blockers to
relax the esophageal and stomach muscles, and use of tricyclic
antidepressants to lower the pain sensation.

[0010] Achalasia is an esophageal disorder wherein the esophagus is less
able to move food towards the stomach and the muscle from the esophagus
to the stomach does not relax as much as it needs to be during
swallowing. Symptoms of achalasia include difficulty swallowing liquids
and solids, regurgitation of food, chest pain, weight loss, heart burn
and cough. Current treatment for achalasia seeks to reduce the pressure
at the lower esophageal sphincter; for example, widening of the lower
esophageal sphincter or injecting the lower esophageal sphincter with
botulimun toxin to paralyze it and prevent spasms. Long-acting nitrates
and calcium channel blockers may also be used to lower the pressure of
the lower esophageal sphincter. Complications of achalasia may include
perforation of the esophagus, reflux, and aspiration of food into the
lungs.

[0011] However, anti-reflux medications only reduce a risk factor for
these conditions; medications to relax the muscles only provide relief to
some patients and their effectiveness overall is not very good; and the
use of antidepressants only treats the associated pain, rather than the
abnormalities themselves. Thus, there exists a need in the art for
alternative and/or additional treatments for spastic or hyperactive
esophageal motor disorders.

SUMMARY OF THE INVENTION

[0012] The following embodiments and aspects thereof are described and
illustrated in conjunction with compositions and methods which are meant
to be exemplary and illustrative, not limiting in scope.

[0013] The present invention provides a method for treating a
gastrointestinal disorder in a subject in need thereof, comprising:
providing an incretin mimetic; and administering a therapeutically
effective amount of the incretin mimetic to the subject. In one
embodiment, the incretin mimetic may be a glucagon-like peptide-1 (GLP-1)
receptor agonist. In a particular embodiment, the GLP-1 receptor agonist
may be an exendin. Particularly useful exendins may include exendin-3,
exendin-4, and functional derivatives thereof. One particularly useful
exendin may be exenatide. GLP-1 receptor agonists that may also be used
include GLP-1 and biologically active forms of GLP-1. In other
embodiments, the GLP-1 receptor agonist may be a purified polypeptide
having an amino acid sequence at least 95% identical to SEQ ID NO: 1. In
still other embodiments, the GLP-1 receptor agonist may be a purified
polypeptide as disclosed by SEQ ID NO: 1 with up to five conservative
amino acid substitutions.

[0014] In various embodiments, the gastrointestinal disorder treated may
be selected from the group consisting of short bowel syndrome, spastic or
hyperactive esophageal motor disorder, and combinations thereof. In
particular embodiments, the spastic or hyperactive esophageal motor
disorder treated may be selected from the group consisting of esophageal
spasm, nutcracker esophagus, achalasia and combinations thereof. In one
particular embodiment, the gastrointestinal disorder treated may be short
bowel syndrome.

[0015] In various embodiments, the therapeutically effective amount
administered may be about 5 micrograms (mcg) to about 10 mcg.
Administering may comprise administering the therapeutically effective
amount twice per day.

[0016] The present invention also provides a method of normalizing bowel
function in a subject in need thereof, comprising: providing an incretin
mimetic; and administering a therapeutically effective amount of the
incretin mimetic to the subject. Normalizing bowel function may comprise
reducing the number of bowel movements in the subject. The incretin
mimetic may be a GLP-1 receptor agonist, as noted above. Further, the
GLP-1 receptor agonists may, be as described herein. The therapeutically
effective amount administered may also be about 5 micrograms (mcg) to
about 10 mcg. Further, administering may also comprise administering the
therapeutically effective amount twice per day.

[0017] The present invention also provides for a kit for treating a
gastrointestinal disorder in a subject in need thereof, comprising: an
incretin mimetic; and instructions to administer a therapeutically
effective amount of the incretin mimetic to the subject. The incretin
mimetic may be a GLP-1 receptor agonist as noted above and described
herein. The gastrointestinal disorder treated by the kit may be selected
from the group consisting of short bowel syndrome, spastic or hyperactive
esophageal motor disorder and combinations thereof. Instructions may
include instructions to administer a therapeutically effective amount of
an incretin mimetic, and particularly, a GLP-1 receptor agonist described
herein twice per day.

[0018] Other features and advantages of the invention will become apparent
from the following detailed description, which illustrate, by way of
example, various features of embodiments of the invention.

DESCRIPTION OF THE INVENTION

[0019] All references cited herein are incorporated by reference in their
entirety as though fully set forth. Unless defined otherwise, technical
and scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this invention
belongs. Singleton et al., Dictionary of Microbiology and Molecular
Biology 3rd ed., J. Wiley & Sons (New York, N.Y. 2001); and March,
Advanced Organic Chemistry Reactions, Mechanisms and Structure 5th
ed., J. Wiley & Sons (New York, N.Y. 2001) provide one skilled in the art
with a general guide to many of the terms used in the present
application.

[0020] One skilled in the art will recognize many methods and materials
similar or equivalent to those described herein, which could be used in
the practice of the present invention. Indeed, the present invention is
in no way limited to the methods and materials described. For purposes of
the present invention, the following terms are defined below.

[0021] "Beneficial results" may include, but are in no way limited to,
lessening or alleviating the severity of the disease condition, lessening
or alleviating symptoms or complications associated with the disease
condition, preventing the disease condition from worsening, curing the
disease condition and prolonging a patient's life or life expectancy.

[0022] "Conditions" and "disease conditions" as used herein may include,
but are in no way limited to any form of short bowel syndrome and spastic
or hyperactive esophageal motor disorders such as esophageal spasms,
nutcracker esophagus and achalasia.

[0023] "Mammal" as used herein refers to any member of the class Mammalia,
including, without limitation, humans and nonhuman primates such as
chimpanzees and other apes and monkey species; farm animals such as
cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and
cats; laboratory animals including rodents such as mice, rats and guinea
pigs, and the like. The term does not denote a particular age or sex.
Thus, adult and newborn subjects, as well as fetuses, whether male or
female, are intended to be included within the scope of this term.

[0024] "Treatment" and "treating" as used herein refer to both therapeutic
treatment and prophylactic or preventative measures, wherein the object
is to prevent, reduce the occurrences or lessen the symptoms associated
with the targeted condition or disease condition even if the treatment is
ultimately unsuccessful. Those in need of treatment include those already
with the condition or disease condition as well as those prone to have
the condition or disease condition or those in whom the condition or
disease condition is to be prevented.

Short Bowel Syndrome

[0025] The present invention is based upon the inventors' discovery that
glucagon-like peptide-1 (GLP-1) receptor agonists are useful for the
treatment of short bowel syndrome. In various embodiments, GLP-1 receptor
agonists may be synthetic or natural exendins such as exendin-3
(HSDGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: 2), or exendin-4
(HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO 3); insulinotropic
fragments of exendin-4 comprising the amino acid sequences:
exendin-4(1-31) (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGP; SEQ ID NO: 4) or
exendin-4(1-31) (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGY; SEQ ID NO: 5); or
functional derivatives thereof as described in U.S. Pat. No. 5,424,286,
herein incorporated by reference as though fully set forth in its
entirety. The '286 Patent also describes additional GLP-1 receptor
agonists that may be appropriate for use in accordance with various
embodiments of the present invention. Additional GLP-1 receptor agonists
and/or exendins and exendin variants that may be appropriate for use with
various embodiments of the present invention include those described by
U.S. Pat. Nos. 6,858,576, 6,872,700, 6,902,744, 6,956,026, 7,297,761
herein incorporated by reference as though fully set forth in their
entirety. One particularly useful GLP-1 receptor agonist is exenatide.
Exenatide (BYETTA®) is currently marketed by Amylin Pharmaceuticals,
Inc. and Eli Lilly and Company as adjunctive therapy to improve glycemic
control in patients with type 2 diabetes mellitus.

[0026] In various embodiments, methods of treating short bowel syndrome in
a subject in need thereof are provided. One method comprises providing a
GLP-1 receptor agonist and administering a therapeutically effective
amount of the GLP-1 receptor agonist to the subject in need of treatment
for short bowel syndrome. The method may further comprise identifying a
subject in need of treatment for short bowel syndrome. The identification
may be made by any individual, for example, a medical practitioner or the
subject himself. In a particular embodiment, the GLP-1 receptor agonist
is exenatide (e.g., BYETTA® exenatide injection).

[0028] Exenatide belongs to a class of drugs referred to as incretin
mimetics. Thus, another method comprises providing an incretin mimetic
and administering a therapeutically effective amount of the incretin
mimetic to a subject in need of treatment for short bowel syndrome. The
method may further comprise identifying a subject in need of treatment
for short bowel syndrome.

[0029] In an alternative embodiment, a naturally produced GLP-1 hormone or
a biologically active forms of GLP-1, such as GLP-1-(7-37) and
GLP-1-(7-36)NH2, may be used to treat short bowel syndrome. The
method may comprise providing a purified quantity of GLP-1 or a
biologically active form of GLP-1 and administering a therapeutically
effective amount of the GLP-1 or the biologically active form of the
GLP-1 to a subject with short bowel syndrome to treat the short bowel
syndrome.

[0030] In another alternate embodiment, a purified polypeptide comprising
SEQ ID NO: 1 may be used to treat short bowel syndrome. Additionally, a
purified polypeptide comprising 38, 37, 36, or 35 consecutive residues of
SEQ ID NO: 1 may be used to treat short bowel syndrome. Further, a
purified polypeptide with an amino acid sequence comprising a sequence at
least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 1
may be used to treat short bowel syndrome.

[0031] In a further embodiment, a purified polypeptide comprising the
amino acid sequence of SEQ ID NO: 1 but with one, two, three, four or
five conservative amino acid substitutions may be used to treat short
bowel syndrome. A conservative amino acid substitution as used herein
refers to a replacement of an amino acid residue with a different residue
having similar physicochemical characteristics; for example, size, charge
and polarity or nonpolarity.

[0032] The present invention also provides methods of normalizing bowel
function in a subject in need thereof. For example, the GLP-1 receptor
agonists or the incretin mimetics described above may be used to reduce
the number of bowel movements in the subject.

Spastic or Hyperactive Esophageal Motor Disorders

[0033] The present invention is also based upon the inventors' discovery
that GLP-1 receptor agonists are useful for the treatment of spastic or
hyperactive esophageal motor disorders. Similar to the treatment of short
bowel syndrome, in various embodiments, GLP-1 receptor agonists used to
treat spastic or hyperactive esophageal motor disorders may be exendins
or exendin derivatives as described above. One particularly useful GLP-1
receptor agonist is exenatide.

[0034] The inventors found that treatment with exenatide reduces
esophageal contraction amplitudes. While not wishing to be bound by any
particular theory, the inventors believe that the reduction in
contraction amplitudes is effective for treating spastic or hyperactive
esophageal motor disorders.

[0035] In various embodiments, methods of treating a spastic or
hyperactive esophageal motor disorder in a subject in need thereof are
provided. One method comprises providing a GLP-1 receptor agonist and
administering a therapeutically effective amount of the GLP-1 receptor
agonist to the subject in need of treatment for a spastic or hyperactive
esophageal motor disorder. The method may further comprise identifying a
subject in need of treatment for a spastic or hyperactive esophageal
motor disorder. In various embodiments, the spastic or hyperactive
esophageal motor disorder treated by the inventive method may be
esophageal spasms, nutcracker esophagus or achalasia. In a particular
embodiment, the GLP-1 receptor agonist used is exenatide

[0036] Another method comprises providing an incretin mimetic and
administering a therapeutically effective amount of the incretin mimetic
to a subject in need of treatment for a spastic or hyperactive esophageal
motor disorder. The method may also comprise identifying a subject in
need of treatment for a spastic or hyperactive esophageal motor disorder.
In various embodiments, the spastic or hyperactive esophageal motor
disorder treated with the incretin mimetic may be esophageal spasms,
nutcracker esophagus or achalasia.

[0037] In an alternative embodiment, a naturally produced GLP-1 hormone or
a biologically active forms of GLP-1, such as GLP-1-(7-37) and
GLP-1-(7-36)NH2, may be used to treat the spastic or hyperactive
esophageal motor disorder. The method may comprise providing a purified
quantity of GLP-1 or a biologically active form of the GLP-1 and
administering a therapeutically effective amount of the GLP-1 or the
biologically active form of the GLP-1 to a subject with a spastic or
hyperactive esophageal motor disorder to treat the spastic or hyperactive
esophageal motor disorder.

[0038] In another alternate embodiment, a purified polypeptide comprising
SEQ ID NO: 1 may be used to treat a spastic or hyperactive esophageal
motor disorder. Additionally, a purified polypeptide comprising 38, 37,
36, or 35 consecutive residues of SEQ ID NO: 1 may be used to treat a
spastic or hyperactive esophageal motor disorder in a subject in need
thereof. Further, a purified polypeptide with an amino acid sequence
comprising a sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%
identical to SEQ ID NO: 1 may be used to treat a spastic or hyperactive
esophageal motor disorder. In a further embodiment, a purified
polypeptide comprising the amino acid sequence of SEQ ID NO: 1, but with
one, two, three, four or five conservative amino acid substitutions may
be used to treat a spastic or hyperactive esophageal motor disorder in a
subject in need thereof.

[0039] In another embodiment, the present invention also provides a method
of reducing esophageal contraction amplitudes in a subject in need
thereof. The method comprises, providing an incretin mimetic or a GLP-1
receptor agonist as described above and administering the incretin
mimetic or the GLP-1 receptor agonist to the subject to reduce the
esophageal contraction amplitudes.

[0040] In other embodiments, the present invention provides pharmaceutical
compositions including a pharmaceutically acceptable excipient along with
a therapeutically effective amount of a GLP-1 receptor agonist or an
incretin mimetic. In a particular embodiment, the GLP-1 receptor agonist
or incretin mimetic is exenatide. "Pharmaceutically acceptable excipient"
means an excipient that is useful in preparing a pharmaceutical
composition that is generally safe, non-toxic, and desirable, and
includes excipients that are acceptable for veterinary use, as well as
for human pharmaceutical use. Such excipients may be solid, liquid,
semisolid, or, in the case of an aerosol composition, gaseous.

[0041] In various embodiments, the pharmaceutical compositions according
to the invention may be formulated for delivery via any route of
administration. "Route of administration" may refer to any administration
pathway known in the art, including but not limited to aerosol, nasal,
oral, transmucosal, transdermal, subcutaneous, or parenteral.
"Parenteral" refers to a route of administration that is generally
associated with injection, including intraorbital, infusion,
intraarterial, intracapsular, intracardiac, intradermal, intramuscular,
intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal,
intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous,
transmucosal, or transtracheal. Via the parenteral route, the
compositions may be in the form of solutions or suspensions for infusion
or for injection, or in the form of lyophilized powders.

[0042] The pharmaceutical compositions according to the invention can also
contain any pharmaceutically acceptable carrier. "Pharmaceutically
acceptable carrier" as used herein refers to a pharmaceutically
acceptable material, composition, or vehicle that is involved in carrying
or transporting a compound of interest from one tissue, organ, or portion
of the body to another tissue, organ, or portion of the body. For
example, the carrier may be a liquid or solid filler, diluent, excipient,
solvent, or encapsulating material, or a combination thereof. Each
component of the carrier must be "pharmaceutically acceptable" in that it
must be compatible with the other ingredients of the formulation. It must
also be suitable for use in contact with any tissues or organs with which
it may come in contact, meaning that it must not carry a risk of
toxicity, irritation, allergic response, immunogenicity, or any other
complication that excessively outweighs its therapeutic benefits.

[0043] The pharmaceutical compositions according to the invention can also
be encapsulated, tableted or prepared in an emulsion or syrup for oral
administration. Pharmaceutically acceptable solid or liquid carriers may
be added to enhance or stabilize the composition, or to facilitate
preparation of the composition. Liquid carriers include syrup, peanut
oil, olive oil, glycerin, saline, alcohols and water. Solid carriers
include starch, lactose, calcium sulfate, dihydrate, terra alba,
magnesium stearate or stearic acid, talc, pectin, acacia, agar or
gelatin. The carrier may also include a sustained release material such
as glyceryl monostearate or glyceryl distearate, alone or with a wax.

[0044] The pharmaceutical preparations are made following the conventional
techniques of pharmacy involving milling, mixing, granulating, and
compressing, when necessary, for tablet forms; or milling, mixing and
filling for producing hard gelatin capsule forms. When a liquid carrier
is used, the preparation will be in the form of a syrup, elixir, emulsion
or an aqueous or non-aqueous suspension. Such a liquid formulation may be
administered directly p.o. or filled into a soft gelatin capsule.

[0045] The pharmaceutical compositions according to the invention may be
delivered in a therapeutically effective amount. The precise
therapeutically effective amount is that amount of the composition that
will yield the most effective results in terms of efficacy of treatment
in a given subject. This amount will vary depending upon a variety of
factors, including but not limited to, the characteristics of the
therapeutic compound (including activity, pharmacokinetics,
pharmacodynamics, and bioavailability), the physiological condition of
the subject (including age, sex, disease type and stage, general physical
condition, responsiveness to a given dosage, and type of medication), the
nature of the pharmaceutically acceptable carrier or carriers in the
formulation, and the route of administration. One skilled in the clinical
and pharmacological arts will be able to determine a therapeutically
effective amount through routine experimentation, for instance, by
monitoring a subject's response to administration of a compound and
adjusting the dosage accordingly. For additional guidance, see Remington:
The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams
& Wilkins PA, USA) (2000).

[0046] Typical dosages of an effective amount of a GLP-1 receptor agonist
or an incretin mimetic, particularly exenatide, may be about 5 micrograms
(mcg) to 10 mcg and may be given subcutaneously twice per day. Dosages
may also be about 10 mcg to about 20 mcg. The dosages may also be given
only once per day or more than twice per day. Dosages can also be in the
ranges recommended by the manufacturer where known therapeutic compounds
are used, and also as indicated to the skilled artisan by the in vitro
responses or responses in animal models. Currently, exenatide is marketed
as BYETTA® exenatide injection by Amylin Pharmaceuticals. In one
embodiment, exenatide may be administered in accordance with the
guidelines provided by Amylin Pharmaceuticals for BYETTA® exenatide
injection. For example, it may be initiated at 5 mcg per dose and
administered twice daily at anytime within a 60 minute period before the
morning and evening meals. It may be increased to 10 mcg twice daily
after one month of therapy. For further guidance, the full prescribing
information for BYETTA® exenatide injection is available from Eli
Lilly and Company. While, BYETTA® exenatide injection is administered
via injection, other forms of administration as described above are
included in the scope of the present invention. Dosages can typically be
reduced by up to about one order of magnitude in concentration or amount
without losing the relevant biological activity. Thus, the actual dosage
may depend upon the judgment of the physician, the condition of the
patient, and the effectiveness of the therapeutic method based, for
example, on the in vitro responsiveness of the relevant primary cultured
cells or histocultured tissue sample, such as biopsied malignant tumors,
or the responses observed in the appropriate animal models, as previously
described.

[0047] The present invention is also directed to kits to treat short bowel
syndrome and/or spastic or hyperactive esophageal motor disorders (e.g.,
esophageal spasms, nutcracker esophagus and achalasia) in a subject in
need thereof. The kit is useful for practicing the inventive method of
treating short bowel syndrome and/or spastic or hyperactive esophageal
motor disorders. The kits include an assemblage of materials or
components, including at least one of the inventive compositions. Thus,
in some embodiments the kit contains a composition including a GLP-1
receptor agonist or an incretin mimetic, particularly exenatide, or a
polypeptide as described above.

[0048] The exact nature of the components configured in the inventive kit
depends on its intended purpose. For example, some embodiments are
configured for the purpose of treating short bowel syndrome in a subject
in need thereof. In other embodiments, the kit is configured for the
purpose of treating spastic or hyperactive esophageal motor disorders. In
one embodiment, the kit is configured particularly for the purpose of
treating mammalian subjects. In another embodiment, the kit is configured
particularly for the purpose of treating human subjects. In further
embodiments, the kit is configured for veterinary applications, treating
subjects such as, but not limited to, farm animals, domestic animals, and
laboratory animals.

[0049] Instructions for use may be included in the kit. "Instructions for
use" typically include a tangible expression describing the technique to
be employed in using the components of the kit to effect a desired
outcome, such as to alleviate symptoms related to short bowel syndrome,
to treat short bowel syndrome, to alleviate symptoms related to spastic
or hyperactive esophageal motor disorders, or to treat spastic or
hyperactive esophageal motor disorders. Optionally, the kit also contains
other useful components such as diluents, buffers, pharmaceutically
acceptable carriers, syringes, catheters, applicators, pipetting or
measuring tools, bandaging materials or other useful paraphernalia as
will be readily recognized by those of skill in the art.

[0050] The materials or components assembled in the kit can be provided to
the practitioner stored in any convenient and suitable ways that preserve
their operability and utility. For example, the components can be in
dissolved, dehydrated, or lyophilized form; they can be provided at room,
refrigerated or frozen temperatures. The components are typically
contained in suitable packaging material(s). As employed herein, the
phrase "packaging material" refers to one or more physical structures
used to house the contents of the kit, such as inventive compositions and
the like. The packaging material is constructed by well known methods,
preferably to provide a sterile, contaminant-free environment. The
packaging materials employed in the kit are those customarily utilized in
treatment of intestinal diseases or injection-type therapies. As used
herein, the term "package" refers to a suitable solid matrix or material
such as glass, plastic, paper, foil, and the like, capable of holding the
individual kit components. Thus, for example, a package can be a syringe
used to contain suitable quantities of an inventive composition
containing a GLP-1 receptor agonist, an incretin mimetic or particularly,
exenatide. The packaging material generally has an external label which
indicates the contents and/or purpose of the kit and/or its components.

EXAMPLES

[0051] The following examples are provided to better illustrate the
claimed invention and are not to be interpreted as limiting the scope of
the invention. To the extent that specific materials are mentioned, it is
merely for purposes of illustration and is not intended to limit the
invention. One skilled in the art may develop equivalent means or
reactants without the exercise of inventive capacity and without
departing from the scope of the invention.

Example 1

[0052] A patient was on total parenteral nutrition with only two feet of
small bowel. Typically, less than three feet of small bowel is too little
to survive on food alone. The patient was having nutritional compromise.
He would experience diarrhea within 15 minutes of eating. Normal eating
habits resulted in experiencing more than 10 bowel movements a day.
Without the i.v. feedings, he would lose ten pounds in one week due to
dehydration. In July 2006, the patient was administered Byetta®
exenatide and on the same day of administration, he did not experience a
bowel movement until six hours after a meal. Since the commencement of
treatment with Byetta® exenatide, he has not required i.v. feeding
and experiences 1-2 solid bowel movements a day. The patient's bowel
health returned to normal and returned to work within one week of
starting treatment with Byetta® exenatide. The patient's nutritional
status improved dramatically and has normalized. The patient has been
using Byetta® exenatide since July 2006.

Example 2

[0053] Short bowel syndrome (SBS) subjects were selected based on clinical
symptoms and history of greater than 50% distal small bowel resection.
Before beginning exenatide treatment, each patient completed a
questionnaire documenting stool frequency and consistency. In addition,
SBS symptoms, CBC, chemistries and BMI were also obtained. An
antroduodenal manometry study was performed during fasting, after
exenatide, and after a subsequent test meal. Each patient was then
started on exenatide 5 to 10 mcg subcutaneously twice a day. Over the
following month the parameters measured at baseline were repeated.

Example 3

[0054] The subjects consisted of 4 males and 1 female, ages 46 to 69
(mean: 57.2). At baseline, all patients had severe diarrhea that ranged
from 7 to 15 bowel movements per day, often occurring within 15 minutes
of eating. After exenatide treatment, all 5 patients had an immediate
improvement in bowel frequency and form. In the most severely affected
patient, the bowel movements reduced from 15 watery bowel movements per
day to 2-3 formed stool. In all subjects, bowel movements were no longer
meal related and often occurred hours after any meal. At baseline
nutritional parameters were stable due to total parenteral nutrition
(TPN) in most cases (n=3). However, after exenatide treatment, all 3
patients no longer needed TPN. Despite the lack of TPN, no weight loss or
biochemical nutritional deterioration was observed in any case. Previous
attempts at ceasing TPN had resulted in immediate and life-threatening
dehydraton and malnutrition. Using normal bowel function as a goal,
subjects described their improvement with exenatide treatment as 65-100%
improved. Antroduodenal manometry in 2 out of 5 subjects demonstrated
continuous low amplitude gastric contractions during fasting which
completely normalized after exenatide.

Example 4

[0055] A patient was administered Byetta® exenatide. A catheter was
placed in the esophagus and esophageal contraction amplitudes were
reduced.

[0056] Various embodiments of the invention are described above in the
Detailed Description. While these descriptions directly describe the
above embodiments, it is understood that those skilled in the art may
conceive modifications and/or variations to the specific embodiments
shown and described herein. Any such modifications or variations that
fall within the purview of this description are intended to be included
therein as well. Unless specifically noted, it is the intention of the
inventors that the words and phrases in the specification and claims be
given the ordinary and accustomed meanings to those of ordinary skill in
the applicable art(s).

[0057] The foregoing description of various embodiments of the invention
known to the applicant at this time of filing the application has been
presented and is intended for the purposes of illustration and
description. The present description is not intended to be exhaustive nor
limit the invention to the precise form disclosed and many modifications
and variations are possible in the light of the above teachings. The
embodiments described serve to explain the principles of the invention
and its practical application and to enable others skilled in the art to
utilize the invention in various embodiments and with various
modifications as are suited to the particular use contemplated.
Therefore, it is intended that the invention not be limited to the
particular embodiments disclosed for carrying out the invention.

[0058] While particular embodiments of the present invention have been
shown and described, it will be obvious to those skilled in the art that,
based upon the teachings herein, changes and modifications may be made
without departing from this invention and its broader aspects and,
therefore, the appended claims are to encompass within their scope all
such changes and modifications as are within the true spirit and scope of
this invention. It will be understood by those within the art that, in
general, terms used herein are generally intended as "open" terms (e.g.,
the term "including" should be interpreted as "including but not limited
to," the term "having" should be interpreted as "having at least," the
term "includes" should be interpreted as "includes but is not limited
to," etc.).